Elsevier

Laboratory Investigation

Volume 93, Issue 11, November 2013, Pages 1184-1193
Laboratory Investigation

Article
Transcriptional upregulation of HIF-1α by NF-κB/p65 and its associations with β-catenin/p300 complexes in endometrial carcinoma cells

https://doi.org/10.1038/labinvest.2013.111Get rights and content
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Abstract

The hypoxia-inducible factor (HIF)-1α, which has a major role in cell adaptation to hypoxia, is mainly regulated at post-translational levels. Recently, HIF-1α mRNA was also shown to be upregulated by several signal pathways under normoxic conditions. Here we focused on relationships of HIF-1α with NF-κB and β-catenin signaling in endometrial carcinomas (Em Cas). Long-term exposure of Ishikawa cells to cobalt chloride (CoCl2), which is known to mimic the effect of hypoxia, caused a decrease in the growth, along with increased HIF-1α protein but not mRNA expression. In contrast, short-term exposure resulted in a rapid and transient increase in HIF-1α mRNA expression along with stabilization of nuclear NF-κB/p65 (p65). Transfection of p65 increased HIF-1α expression through activation of the promoter, whereas overexpression of HIF-1α also activated NF-κB-dependent transcription, indicating the existence of a positive feedback loop. In addition, HIF-1α was indirectly associated with nuclear β-catenin through interactions with p300, leading to slight enhancement of both HIF-1α- and β-catenin-mediated transcriptional activity. In clinical samples, biphasic upregulation of HIF-1α expression was observed in normal endometrial glandular components during the menstrual cycle, with the labeling indices showing significantly higher values in the early secretory stage. Significantly higher values for phosphorylated p65 and nuclear β-catenin were also observed in HIF-1α-positive than -negative lesions of Em Cas, in contrast to significantly lower Ki-67 status. These data therefore suggest that transcriptional associations with HIF-1α and NF-κB, as well as β-catenin/p300 complexes, may contribute to modulation of changes in tumor cell kinetics in response to a hypoxic condition in Em Cas.

β-catenin
endometrial carcinoma
HIF-1α
hypoxia
NF-κB

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Supplementary Information accompanies the paper on the Laboratory Investigation website

In endometrial carcinoma, hypoxia-inducible factor-1α (HIF-1α) expression correlates with tumor aggressiveness and is a regulator of tumor cell adaption to radiation therapy and hypoxia. This study reveals that transcriptional association of HIF-1α and NF-κB, as well as β-catenin/p300 complexes, may contribute to changes in tumor cell kinetics in response to microenvironmental hypoxia in endometrial carcinoma.

Supplementary information The online version of this article (doi:10.1038/labinvest.2013.111) contains supplementary material, which is available to authorized users.